Pathophysiology Of Dilated Cardiomyopathy Research Articles

Investigating the role of NPR1 in dilated cardiomyopathy and its potential as a therapeutic target for glucocorticoid therapy.

Background: Dilated cardiomyopathy (DCM), a specific form of cardiomyopathy, frequently presents clinically with either left ventricular or biventricular enlargement, often leading to progressive heart failure. In recent years, the application of bioinformatics technology to scrutinize the onset, progression, and prognosis of DCM has emerged as a fervent area of interest among scholars globally. Methods: In this study, core genes closely related to DCM were identified through bioinformatics analysis, including weighted gene co expression network analysis (WGCNA) and single sample gene set enrichment analysis (ssGSEA) and so on. The correlation was verified through experiments on DCM patients, DCM rat models, and core gene knockout mice. Subsequently, the effects of glucocorticoids on DCM and the regulation of core genes were observed. Result: In the present study, natriuretic peptide receptor 1 (NPR1) was identified as a core gene associated with DCM through WGCNA and ssGSEA. Significant impairment of cardiac and renal function was observed in both DCM patients and rats, concomitant with a notable reduction in NPR1 expression. NPR1 KO mice displayed symptomatic manifestations of DCM, underscoring the pivotal role of NPR1 in its pathogenesis. Notably, glucocorticoid treatment led to substantial improvements in cardiac and renal function, accompanied by an upregulation of NPR1 expression. Discussion: These findings highlight the critical involvement of NPR1 in the pathophysiology of DCM and its potential as a key target for glucocorticoid-based DCM therapy. The study provides a robust theoretical and experimental foundation for further investigations into DCM etiology and therapeutic strategies.

A concise review on the role of MIR100HG in human disorders.

MIR100HG is a long non-coding RNA (lncRNA) encoded by a locus on chr11:122,028,203-122,556,721. This gene can regulate cell proliferation, apoptosis, cell cycle transition and cell differentiation. MIR100HG was firstly identified through a transcriptome analysis and found to regulate differentiation of human neural stem cells. It is functionally related with a number of signalling pathways such as TGF-β, Wnt, Hippo and ERK/MAPK signalling pathways. Dysregulation of MIR100HG has been detected in a diversity of cancers in association with clinical outcomes. Moreover, it has a role in the pathophysiology of dilated cardiomyopathy, intervertebral disk degeneration and pulmonary fibrosis. The current study summarizes the role of these lncRNAs in human disorders.

Malperfusion in dilated cardiomyopathy: One more link in the pathologic chain?

Dilated cardiomyopathy (DCM) is considered the primary non-ischemic heart disease, but there are controversial data regarding the microcirculatory disturbance in these patients. While the major epicardial vessels are always intact in these patients, the malperfusion of the myocardium of the left ventricle (LV) may be present, and the role of this malperfusion in the progression of the disease is not clear. The non-invasive echocardiographic assessment of the coronary blood flow reveals that it may be increased at rest and decreased during pharmacological stress, leading to a decreased coronary flow reserve.1 Beyond echocardiographic studies, microvascular dysfunction in DCM has been previously investigated with various imaging modalities. Bietenbeck M. et al. performed the quantitative myocardial first-pass perfusion cardiovascular magnetic resonance (CMR) imaging and coronary sinus flow measurements at rest and during maximal vasodilatation which is a well-validated approach for the quantification of global myocardial blood flow in CMR. The blood flow parameters were reduced at rest and during stress in both groups of patients with DCM and hypertrophic cardiomyopathy.2 Interestingly, in another study, it was shown that myocardial blood flow assessed by the CMR in DCM could be elevated at rest with a substantial decrease during the stress-test with adenosine. This corresponds well with the previous echocardiographic findings and also can reflect the possible stress-induced stunning instead of chronic hypoperfusion in DCM.3 Another promising in microcirculation evaluation, though not a fully available modality, is PET. In a study by Yamaguchi et al., the authors observed the regional 18-fluorodesoxiglucose uptake in all patients with ischemic cardiomyopathy in the fasting state, while patients with DCM showed variable patterns of uptake. Nevertheless, when going to glucose loading state, the DCM patients demonstrated mostly non-reversing patterns of uptake, which allows PET to distinguish DCM from ischemic cardiomyopathy.4 (99 m)Tc-methoxy-isobutyl-isonitrile and (123)I-15-(p-iodophenyl)-3(R,S)-methylpentadecanoic acid dual single photon emission computed tomography also provides valuable data on perfusion-metabolism mismatches, which carry the prognostic role in DCM.5 Myocardial contrast echocardiography (MCE) being a more simple, bedside method has been previously found to be helpful in differentiating the DCM and ischemic heart disease in patients with acute onset of heart failure.6 However, another group of authors has the confronting results: the contrast replenishment rate was similar in patients with coronary artery disease and without it.7 In this issue of the Journal of Clinical Ultrasound Sha Tang et al, for the first time the MCE was combined with speckle tracking strain analysis in a layer-specific manner in patients with DCM and compared with the same parameters in healthy volunteers.8 While the poor global and regional LV systolic function assessed by speckle tracking strain in DCM patients in comparison to healthy subjects is awaited, the authors performed the comprehensive analysis of the interaction between segmental parameters by dividing the myocardium into standard segments plus three layers in each segment. Therefore, the data on gradients in strain and perfusion parameters becomes the mainstay of this study. The idea of layer-specific strain analysis is not new, but still can be regarded as a pure experimental method with no clinical implication. For example, in the work by Nagata Y et al. the authors offer Endo/Epi strain ratio for gradient assessment.9 Therefore, the authors demonstrated an interesting correlation between MCE perfusion and longitudinal function at rest in DCM patients with the diffuse pattern of impairment in all segments and layers. Considering the aforementioned CMR-based and PET-based studies, which showed a substantial decrease in coronary flow reserve between rest and stress, the MCE with pharmacological stress could be the rational development of basic ideas, presented in this study. Moreover, the dynamic nature of MCE can give the opportunity for dynamic malperfusion assessment in patients with DCM during stress. In addition, new insights into the pathophysiology of DCM may provide the basis for new clinical trials of various agents, intended to restore the damaged microcirculatory link in the chain of global LV deterioration. The authors have nothing to disclosure. Open Access funding enabled and organized by Projekt DEAL. Not applicable.

Screening for Mitochondrial tRNA Mutations in 318 Patients with Dilated Cardiomyopathy

Objectives: Dilated cardiomyopathy (DCM) is a complex cardiovascular disease with unknown etiology. Although nuclear genes play active roles in DCM, mitochondrial dysfunction was believed to be involved in the pathogenesis of DCM. The objective of this study was to analyze the association between mitochondrial tRNA (mt-tRNA) mutations and DCM. Materials and Methods: We performed a mutational analysis of mt-tRNA genes in a cohort of 318 patients with DCM and 200 age- and gender-matched control subjects. To further assess their pathogenicity, phylogenetic analysis and mitochondrial functions including mtDNA copy number, ATP, and ROS were analyzed. Results: Seven possible pathogenic mutations, i.e., MT-TL1 3302A>G, MT-TI 4295A>G, MT-TM 4435A>G, MT-TA 5655T>C, MT-TH 12201T>C, MT-TE 14692A>G, and MT-TT 15927G>A, were identified in the DCM group but were absent in controls. These mutations occurred at extremely conserved nucleotides of corresponding tRNAs and led to the failure in tRNAs metabolism. Moreover, a significant reduction in ATP and mtDNA copy number and a marked increase in ROS level were observed in polymononuclear leukocytes (PMNs) derived from the DCM patients carrying these mt-tRNA mutations, suggesting that these mutations may cause mitochondrial dysfunction that was responsible for DCM. Conclusions: Our data indicated that mt-tRNA mutations may be the molecular basis for DCM, which provides novel insights into the pathophysiology of DCM that manifested as mitochondrial dysfunction.

Genome wide association analysis in dilated cardiomyopathy revealed two new susceptibility loci for systolic heart failure

Abstract We conducted the largest Genome Wide Association Study performed so far in Dilated Cardiomyopathy (DCM), a leading cause of systolic heart failure and cardiovascular death. Using a discovery phase of 2,719 cases and 4,440 controls and a replication phase of 584 independent cases and 966 controls, we identified and replicated two new DCM-associated loci, one on chromosome 3p (meta-analysis OR = 1.36 [1.25 - 1.48], p=5.3 10–13) and the second on chromosome 22q (meta-analysis OR = 1.33 [1.22 - 1.46], p=5.0 10–10), while confirming the two previously identified DCM loci on chromosome 10 and 1, BAG3 and HSPB7. We estimated the global heritability to 31% ± 8%. The genetic risk score constructed from the number of lead risk-alleles at these 4 loci revealed a 27% risk increased in individuals with 8 risk-alleles compared to the 5 risk alleles reference group (OR = 1.27 [1.14–1.42]). The two association signals were then fine-mapped by combining in silico and functional genomics investigations (as 4C-sequencing on iPSC-derived cardiomyocytes). While a few genes remain candidates at the second locus and deserve further investigations, our work clearly identified one gene as responsible for the association at the first locus whose role in the pathophysiology of DCM is supported by recent observations in human and mice. As the biological pathway in which this gene is involved is a potential target for pharmacological agents, our finding opens novel therapeutic perspectives for treating or preventing heart failure. We are convinced that these results provide new findings that add both on the understanding of the genetic architecture of heart failure and on potential new players involved in the pathophysiology of this devastating disease. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): GENMED Laboratory of Excellence on Medical Genomics, DETECTIN-HF project (ERA-CVD framework), Assistance Publique-Hôpitaux de Paris, Délégation à la recherche clinique, the “Fondation LEDUCQ”, the PROMEX charitable foundation, the Société Française de Cardiologie/Fédération Française de Cardiologie, the Deutsche Forschungsgemeinschaft, The Federal Ministry of Education and Research and the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania, The German Center for Cardiovascular Research (DZHK), Hospitals NIHR Biomedical Research Centre, NWO VENI grant (no. 016.176.136)

Abstract 363: Systems Network Genomic Analysis Reveals the Role Of MURC/Cavin-4 in Cardiac Ischemia/reperfusion Injury

Background: Ischemia/reperfusion (I/R) injury is a critical issue in the development of treatment strategies for ischemic heart disease. Muscle-restricted coiled-coil protein (MURC)/Cavin-4, which is a component of caveolae, is involved in the pathophysiology of dilated cardiomyopathy and cardiac hypertrophy. However, the role of MURC in cardiac I/R injury remains unknown. Objective: To elucidate the role of MURC in cardiac I/R injury. Methods and Results: The systems network genomic analysis based on PC-corr network inference on microarray data between wild-type and MURC knockout (KO) mouse hearts described a network of discriminating genes associated with reactive oxygen species (ROS). To demonstrate the prediction, we investigated the effect of MURC deletion in cardiac I/R injury. MURC deletion in IR-injured mouse hearts decreased infarct size and preserved heart contraction with the inhibition of ROS production and ROS-related gene expressions such as EGR1 and DDIT4 as well as EGR1 protein level. PC-corr network inference integrated with a protein-protein interaction network prediction showed that MURC is also involved in the apoptotic pathway. We confirmed the upregulated activity of STAT3, which is a transcription factor of anti-apoptotic signaling, with the increase of BCL2 mRNA expression and protein level and the decrease of cleaved Caspase 3 protein level in MURC KO compared with WT mouse hearts after I/R. TUNEL assay showed that MURC modulates the apoptosis in cardiomyocytes exposed to hydrogen peroxide. STAT3 inhibitor cancelled the cardioprotective effect of MURC deletion in I/R-injured heart and the anti-apoptotic effect of MURC knockdown in cardiomyocytes. Conclusions: Our findings suggest that MURC plays a pivotal role in the regulation of ROS-induced cell death and STAT3-meditated anti-apoptotic signaling in cardiac I/R injury. MURC may be a therapeutic target for cardiac I/R injury.

Systems Network Genomic Analysis Reveals Cardioprotective Effect of MURC/Cavin-4 Deletion Against Ischemia/Reperfusion Injury.

BackgroundIschemia/reperfusion (I/R) injury is a critical issue in the development of treatment strategies for ischemic heart disease. MURC (muscle‐restricted coiled‐coil protein)/Cavin‐4 (caveolae‐associated protein 4), which is a component of caveolae, is involved in the pathophysiology of dilated cardiomyopathy and cardiac hypertrophy. However, the role of MURC in cardiac I/R injury remains unknown.Methods and ResultsThe systems network genomic analysis based on PC‐corr network inference on microarray data between wild‐type and MURC knockout mouse hearts predicted a network of discriminating genes associated with reactive oxygen species. To demonstrate the prediction, we analyzed I/R‐injured mouse hearts. MURC deletion decreased infarct size and preserved heart contraction with reactive oxygen species–related molecule EGR1 (early growth response protein 1) and DDIT4 (DNA‐damage‐inducible transcript 4) suppression in I/R‐injured hearts. Because PC‐corr network inference integrated with a protein–protein interaction network prediction also showed that MURC is involved in the apoptotic pathway, we confirmed the upregulation of STAT3 (signal transducer and activator of transcription 3) and BCL2 (B‐cell lymphoma 2) and the inactivation of caspase 3 in I/R‐injured hearts of MURC knockout mice compared with those of wild‐type mice. STAT3 inhibitor canceled the cardioprotective effect of MURC deletion in I/R‐injured hearts. In cardiomyocytes exposed to hydrogen peroxide, MURC overexpression promoted apoptosis and MURC knockdown inhibited apoptosis. STAT3 inhibitor canceled the antiapoptotic effect of MURC knockdown in cardiomyocytes.ConclusionsOur findings, obtained by prediction from systems network genomic analysis followed by experimental validation, suggested that MURC modulates cardiac I/R injury through the regulation of reactive oxygen species–induced cell death and STAT3‐meditated antiapoptosis. Functional inhibition of MURC may be effective in reducing cardiac I/R injury.

Myocardin ablation in a cardiac-renal rat model

Cardiorenal syndrome is defined by primary heart failure conditions influencing or leading to renal injury or dysfunction. Dilated cardiomyopathy (DCM) is a major co-existing form of heart failure (HF) with renal diseases. Myocardin (MYOCD), a cardiac-specific co-activator of serum response factor (SRF), is increased in DCM porcine and patient cardiac tissues and plays a crucial role in the pathophysiology of DCM. Inhibiting the increased MYOCD has shown to be partially rescuing the DCM phenotype in porcine model. However, expression levels of MYOCD in the cardiac tissues of the cardiorenal syndromic patients and the effect of inhibiting MYOCD in a cardiorenal syndrome model remains to be explored. Here, we analyzed the expression levels of MYOCD in the DCM patients with and without renal diseases. We also explored, whether cardiac specific silencing of MYOCD expression could ameliorate the cardiac remodeling and improve cardiac function in a renal artery ligated rat model (RAL). We observed an increase in MYOCD levels in the endomyocardial biopsies of DCM patients associated with renal failure compared to DCM alone. Silencing of MYOCD in RAL rats by a cardiac homing peptide conjugated MYOCD siRNA resulted in attenuation of cardiac hypertrophy, fibrosis and restoration of the left ventricular functions. Our data suggest hyper-activation of MYOCD in the pathogenesis of the cardiorenal failure cases. Also, MYOCD silencing showed beneficial effects by rescuing cardiac hypertrophy, fibrosis, size and function in a cardiorenal rat model.

Galectin-3 deficiency ameliorates fibrosis and remodeling in dilated cardiomyopathy mice with enhanced Mst1 signaling.

Dilated cardiomyopathy (DCM) is a major cause of heart failure without effective therapy. Fibrogenesis plays a key role in the development of DCM, but little is known of the expression of the profibrotic factor galectin-3 (Gal-3) and its role in DCM pathophysiology. In a mouse DCM model with transgenic (TG) overexpression of mammalian sterile 20-like kinase 1 (Mst1), we studied Gal-3 expression and effects of the Gal-3 inhibitor modified citrus pectin (MCP) or Gal-3 gene knockout (KO). Gal-3 deletion in TG mice (TG/KO) was achieved by crossbreeding Mst1-TG mice with Gal-3 KO mice. The DCM phenotype was assessed by echocardiography and micromanometry. Cardiac expression of Gal-3 and fibrosis were determined. The cardiac transcriptome was profiled by RNA sequencing. Mst1-TG mice at 3-8 mo of age exhibited upregulated expression of Gal-3 by ~40-fold. TG mice had dilatation of cardiac chambers, suppressed left ventricular (LV) ejection fraction, poor LV contractility and relaxation, a threefold increase in LV collagen content, and upregulated fibrotic genes. Four-month treatment with MCP showed no beneficial effects. Gal-3 deletion in Mst1-TG mice attenuated chamber dilatation, organ congestion, and fibrogenesis. RNA sequencing identified profound disturbances by Mst1 overexpression in the cardiac transcriptome, which largely remained in TG/KO hearts. Gal-3 deletion in Mst1-TG mice, however, partially reversed the dysregulated transcriptional signaling involving extracellular matrix remodeling and collagen formation. We conclude that cardiac Mst1 activation leads to marked Gal-3 upregulation and transcriptome disturbances in the heart. Gal-3 deficiency attenuated cardiac remodeling and fibrotic signaling. NEW & NOTEWORTHY We found in a transgenic mouse dilated cardiomyopathy (DCM) model a pronounced upregulation of galectin-3 in cardiomyocytes. Galectin-3 gene deletion reduced cardiac fibrosis and fibrotic gene profiles and ameliorated cardiac remodeling and dysfunction. These benefits of galectin-3 deletion were in contrast to the lack of effect of treatment with the galectin-3 inhibitor modified citrus pectin. Our study suggests that suppression of galectin-3 mRNA expression could be used to treat DCM with high cardiac galectin-3 content.

Rare genetic mutations in Pakistani patients with dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a leading cause of heart failure, and heart transplantation globally. There is enlargement of left ventricle of the heart impairing the systolic function in this disorder. The involvement of genetic factors in the pathogenesis of DCM has been reported in up to 50% of the cases. However, due to the complexity and heterogeneity of the disease, the complete pathophysiology remains unclear. In this study, whole exomes of five unrelated patients of idiopathic DCM were sequenced to an average depth of 100× using Illumina HiSeq4000 system. The analysis of the data with in silico tools SIFT, Polyphen2, and CADD showed 494 rare (AF < 1.0%) missense SNVs predicted as deleterious. Detrimental variants in genes highly expressed in cardiac tissue included 3 rare allele frequency loss-of-function SNVs in C2orf40, MYOM3, and TMED4 genes, a homozygous frameshift insertion in RTKN2, and a splice site homozygous deletion in SLC6A6 in at least one of the patients. The stop-gained SNV rs143187236 of MYOM3 (myomesin 3) was found in perfect linkage disequilibrium (r2 = 1.0) with its neighboring missense SNV rs149105212 in two of the patients, representing the role of myomesin 3 in pathophysiology of DCM. Allele frequency comparison showed three variants rs375563861 (C2orf40), rs143187236 (MYOM3), and rs564181443 (RTKN2) having 3 fold or higher allele frequency in South Asians than in the global populations. The identified pathogenic variants can be used in risk assessment and precision therapy in DCM patients.

HUMAN EPIDIDYMIS PROTEIN 4 IS A NOVEL FIBROSIS MARKER TO PREDICT PATHOLOGICAL CARDIAC REMODELING AND ADVERSE OUTCOMES IN PATIENTS WITH DILATED CARDIOMYOPATHY

The prognosis of dilated cardiomyopathy (DCM) remains unfavorable because of progressive depression of cardiac function. Cardiac interstitial fibrosis plays a crucial role in the pathophysiology of DCM. Human Epididymis Protein 4 (HE-4), novel fibrosis marker, is specifically expressed in activated

Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy

Aims Dilated cardiomyopathy (DCM) is an important cause of heart failure with a strong familial component. We performed an exome-wide array-based association study (EWAS) to assess the contribution of missense variants to sporadic DCM. Methods and results Overall, 116,855 single nucleotide variants (SNVs) were analyzed in 2796 DCM patients and 6877 control subjects from 6 populations of European ancestry. We confirmed two previously identified associations with SNVs in BAG3 and ZBTB17 and discovered six novel DCM-associated loci (Q-value Conclusion We identified eight loci independently associated with sporadic DCM. Overlap between susceptibility gene and familial DCM causing gene suggests a continuum of effect size, or penetrance, in DCM associated molecular variants. The functions of the best candidate genes at these loci also suggest that proteostasis regulation might play a role in DCM pathophysiology.

Truncating mutations on myofibrillar myopathies causing genes as prevalent molecular explanations on patients with dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is one of the leading causes of heart failure with high morbidity and mortality. More than 40 genes have been reported to cause DCM. To provide new insights into the pathophysiology of dilated cardiomyopathy, a next-generation sequencing (NGS) workflow based on a panel of 48 cardiomyopathies-causing genes was used to analyze a cohort of 222 DCM patients. Truncating variants were detected on 63 unrelated DCM cases (28.4%). Most of them were identified, as expected, on TTN (29 DCM probands), but truncating variants were also identified on myofibrillar myopathies causing genes in 17 DCM patients (7.7% of the DCM cohort): 10 variations on FLNC and 7 variations on BAG3 . This study confirms that truncating variants on myofibrillar myopathies causing genes are frequently associated with dilated cardiomyopathies and also suggest that FLNC mutations could be considered as a common cause of dilated cardiomyopathy. Molecular approaches that would allow to detect systematically truncating variants in FLNC and BAG3 into genetic testing should significantly increase test sensitivity, thereby allowing earlier diagnosis and therapeutic intervention for many patients with dilated cardiomyopathy.

Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy.

AimsDilated cardiomyopathy (DCM) is an important cause of heart failure with a strong familial component. We performed an exome-wide array-based association study (EWAS) to assess the contribution of missense variants to sporadic DCM.Methods and results116,855 single nucleotide variants (SNVs) were analyzed in 2796 DCM patients and 6877 control subjects from 6 populations of European ancestry. We confirmed two previously identified associations with SNVs in BAG3 and ZBTB17 and discovered six novel DCM-associated loci (Q-value<0.01). The lead-SNVs at novel loci are common and located in TTN, SLC39A8, MLIP, FLNC, ALPK3 and FHOD3. In silico fine mapping identified HSPB7 as the most likely candidate at the ZBTB17 locus. Rare variant analysis (MAF<0.01) demonstrated significant association for TTN variants only (P = 0.0085). All candidate genes but one (SLC39A8) exhibit preferential expression in striated muscle tissues and mutations in TTN, BAG3, FLNC and FHOD3 are known to cause familial cardiomyopathy. We also investigated a panel of 48 known cardiomyopathy genes. Collectively, rare (n = 228, P = 0.0033) or common (n = 36, P = 0.019) variants with elevated in silico severity scores were associated with DCM, indicating that the spectrum of genes contributing to sporadic DCM extends beyond those identified here.ConclusionWe identified eight loci independently associated with sporadic DCM. The functions of the best candidate genes at these loci suggest that proteostasis regulation might play a role in DCM pathophysiology.

Role of cardiac TBX20 in dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is an important cause of heart failure and sudden cardiac death worldwide. Transcription factor TBX20 has been shown to play a crucial role in cardiac development and maintenance of adult mouse heart. Recent studies suggest that TBX20 may have a role in pathophysiology of DCM. In the present study, we examined TBX20 expression in idiopathic DCM patients and in an animal model of cardiomyopathy, and studied its correlation with echocardiographic indices of LV function. Endomyocardial biopsies (EMBs) from intraventricular septal from the right ventricle region were obtained from idiopathic DCM patients (IDCM, n = 30) and from patients with ventricular septal defect (VSD, n = 14) with normal LVEF who served as controls. An animal model of DCM was developed by right renal artery ligation in Wistar rats. Cardiac TBX20 mRNA levels were measured by real-time PCR in IDCM, controls, and in rats. The role of DNA promoter methylation and copy number variation (CNVs) in regulating TBX20 gene expression was also investigated. Cardiac TBX20 mRNA levels were significantly increased (8.9 fold, p < 0.001) in IDCM patients and in RAL rats as compared to the control group. Cardiac TBX20 expression showed a negative correlation with LVEF (r = -0.71, p < 0.001) and a positive correlation with left ventricular end-systolic volume (r = 0.39, p = 0.038). No significant difference in TBX20 CNVs and promoter methylation was observed between IDCM patients and control group. Our results suggest a potential role of TBX20 in pathophysiology of DCM.

Effect of Physiological Determinants and Cardiac Disease on Plasma Adiponectin Concentrations in Dogs

BackgroundIn humans, a high concentration of adiponectin is associated with a favorable cardiovascular risk profile whereas, in patients with heart failure (HF), a high concentration of adiponectin is associated with a less favorable prognosis.Hypothesis/ObjectivesTo evaluate the physiological determinants of plasma adiponectin concentration in dogs and the influence of heart disease, myxomatous mitral valve disease (MMVD), and dilated cardiomyopathy (DCM).AnimalsOne hundred and fourteen client‐owned dogs and 9 Beagles from the research colony of the Clinical Veterinary Unit of the University of Liège.MethodsWe prospectively measured circulating adiponectin concentration in healthy control dogs (n = 77), dogs with MMVD (n = 22) and dogs with DCM (n = 15) of various degrees of severity. Diagnosis was confirmed by Doppler echocardiography. Plasma adiponectin concentration was measured by a canine‐specific sandwich ELISA kit.ResultsAn analysis of covariance showed an association between adiponectin concentration and age, neuter status, and heart disease. No association between adiponectin concentration and class of HF, sex, body condition score, body weight, circadian rhythm, or feeding was found. Plasma adiponectin concentration was negatively correlated with age (P = .001). Adiponectin was lower in neutered (P = .008) compared to intact dogs. Circulating adiponectin concentration was increased in dogs with DCM compared to healthy dogs (P = .018) and to dogs with MMVD (P = .014).Conclusions and Clinical ImportanceAge and neutering negatively influence circulating adiponectin concentration. Plasma adiponectin concentration increased in dogs with DCM. Additional research is required to investigate if this hormone is implicated in the pathophysiology of DCM and associated with clinical outcome.

Endothelin 1 gene as a modifier in dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a myocardial disease of unknown etiology with left ventricular dilatation and impaired myocardial contractility leading to heart failure. It is considered to be a multifactorial disorder with the interplay of both genetic and environmental factors. One of the possible genes implicated in DCM is endothelin 1 (EDN1). The genetic variants of EDN1 may be involved in the pathophysiology of DCM hence the entire EDN1 gene was screened to examine for the possible genotypic associations with DCM. A total of 115 DCM patients and 250 control subjects were included in the present study. PCR based SSCP analysis was carried out followed by commercial sequencing. Screening of EDN1 revealed two common and two rare polymorphisms. Allelic and genotypic frequencies were estimated in patient and control groups by appropriate statistical tests. The heterozygotes of insertion variation (+138A) were found to exhibit four-fold increase risk to DCM (OR=4.12, 95% CI 2.10–8.08; p=0.0001). The two rare variants (G>A transition (rs150035515) at c.90 and C>T transition (rs149399492) at c.119) observed in the present study were found to be unique in DCM. The secondary mRNA structures of these variations were found to have less free energy than wild type. The haplotype analysis revealed 4A–T to be risk haplotype for DCM (OR 5.90, 95% CI 2.29–15.25, p=0.0001). In conclusion, EDN1 polymorphisms (+138A, A30A, T40I) appear to play a significant role in the pathogenesis of DCM, as they influence the stability of protein. The increased EDN1 production may lead to constriction of coronary arteries, reducing coronary blood flow which may in turn increase the load on left ventricle, impairing contractility of the heart resulting in a DCM phenotype, an end stage of heart failure.

LEFT VENTRICULAR TONIC CONTRACTION FREQUENTLY PRECEDES DILATION IN CARDIOMYOPATHY OF DUCHENNE MUSCULAR DYSTROPHY

Dilated cardiomyopathy (DCM) inevitably afflicts patients with Duchenne muscular dystrophy (DMD). Understanding of the molecular pathophysiology of DCM in DMD has advanced, but correlation of these advances with clinical disease is lacking. We sought to identify echocardiographic changes that occur

The immune protein MD-2 is a novel independent predictor for long term mortality in dilated cardiomyopathy and non-inferior to nt-pro BNP

Background: Myeloid Differentiation protein 2 (MD-2) is strongly involved in activation of the innate immune receptor Toll-Like Receptor 4 (TLR4). Its role in cardiac diseases is unknown. Since cardiac inflammation is often associated with heart failure, we investigated in the present study the impact of MD-2 level at first hospital admission in patients with Dilated Cardiomyopathy (DCM) on long term mortality. Methods and results: We included 174 patients between 2005 and 2011 with biopsy-proven DCM in our study. MD-2 protein expression in serum from patients was quantified by ELISA (USCN Life Science, USA) and nt-pro brain natriuretic peptide (nt-pro BNP) level were quantified during routine diagnostics at first hospital admission. The primary end point of this study was all-cause mortality. Information on vital status of patients was obtained from official resident data files. For descriptive statistics the study population was divided into two groups according to the patients' MD-2 measurement (≥ and < median of all patients). Survival analysis was done calculating Kaplan–Meier curves and log-rank test was used for curve comparison. Multivariable Cox regression models were applied to assess the association between MD-2 level and all-cause mortality, with adjustment for age and cardiovascular risk factors. A value of p < 0.05 was considered statistically significant. All-cause mortality in DCM patients with MD-2 level ≥ overall median (302.44 ng/ml) was strongly associated with increased mortality when compared to patients with MD-2 level < overall median (31.0% versus 8.1%, p<0.001). Multivariable Cox regression analyses demonstrate, that this effect was independent from age, LV ejection fraction and other cardiovascular risk factors including diabetes, BMI, arterial systolic and diastolic blood pressure and smoking with a hazard ratio of 1.004 (p<0.001) for MD-2 as continuous variable. ROC analyses showed no statistically difference between prediction of mortality regarding MD-2 vs. nt-pro BNP (AUC: 0.79 versus 0.74, p=0.40). Conclusion: MD-2, quantified at first hospital admission, is an independent predictor for mortality in DCM and is non-inferior to nt-pro BNP suggesting a relevant role of this protein in the pathophysiology of DCM.

Identification of heart rate–associated loci and their effects on cardiac conduction and rhythm disorders

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.